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WO2003037360A1 - Methode permettant de reparer la muqueuse du tractus gastro-intestinal ainsi que d'en stimuler la regeneration et composition a cet effet - Google Patents

Methode permettant de reparer la muqueuse du tractus gastro-intestinal ainsi que d'en stimuler la regeneration et composition a cet effet Download PDF

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Publication number
WO2003037360A1
WO2003037360A1 PCT/US2002/034902 US0234902W WO03037360A1 WO 2003037360 A1 WO2003037360 A1 WO 2003037360A1 US 0234902 W US0234902 W US 0234902W WO 03037360 A1 WO03037360 A1 WO 03037360A1
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composition
oil
weight
edible
beeswax
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PCT/US2002/034902
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Rongxiang Xu
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Priority to CA2464152A priority Critical patent/CA2464152C/fr
Priority to EP02773952A priority patent/EP1439847B1/fr
Priority to JP2003539703A priority patent/JP4464133B2/ja
Priority to AT02773952T priority patent/ATE510549T1/de
Publication of WO2003037360A1 publication Critical patent/WO2003037360A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A23L33/11—Plant sterols or derivatives thereof, e.g. phytosterols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A—HUMAN NECESSITIES
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    • A61K36/18—Magnoliophyta (angiosperms)
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    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/539—Scutellaria (skullcap)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
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    • A61K36/66—Papaveraceae (Poppy family), e.g. bloodroot
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
    • A61K36/718—Coptis (goldthread)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K36/18—Magnoliophyta (angiosperms)
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    • A—HUMAN NECESSITIES
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    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/889—Arecaceae, Palmae or Palmaceae (Palm family), e.g. date or coconut palm or palmetto
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/899—Poaceae or Gramineae (Grass family), e.g. bamboo, corn or sugar cane
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4875—Compounds of unknown constitution, e.g. material from plants or animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • the present invention relates to methods and compositions for tissue repair and regeneration, and more particularly to methods and compositions for protecting the mucosal tissue from damages caused by irritants and for promoting repair and regeneration of damaged or dysfunctional mucosal tissue in the gastrointestinal tract, especially for the treatment of gastrointestinal disorders such as gastritis, peptic ulcer, reflux esophagitis, dyspepsia, and gastric cancer, and the restoration of the physiological structure and function to the mucosal tissue.
  • gastrointestinal disorders such as gastritis, peptic ulcer, reflux esophagitis, dyspepsia, and gastric cancer
  • Mucosal tissues are membranes that line body cavities such mouth, nose, eyelids and sexual organs, and canals such as alimentary canals (e.g., the gastrointestinal (Gl) tract) and the respiratory tract. Since mucosa is exposed to the external air, it secrets mucus to moisten and protect itself from adversary effects of environmental elements.
  • Gl gastrointestinal
  • Mucosa is primarily comprised of epithelial cells that are attached to the basement membrane. Unlike the mucosal tissue of the inner surface of the eyelids, the epithelial cells which line the inside of the stomach are exposed to much harsher conditions, e.g., acid (i.e., hydrochloric acid), sometimes alcohol, enzymes (e.g., pepsin) for digesting food, and waste generated therefrom. Mucous secretion essentially protects the cells on the inside of the stomach and duodenum from damage by acid or enzymes, for example by presenting bicarbonate to neutralize some of the effects of acid on the stomach's inner lining, and inhibitors to block the enzymatic activity. Once the mucous secretions of the epithelial cells stop, the inner lining of the stomach or duodenum would eventually be eroded by the combined action of acid and enzymes, leading to ulcer.
  • acid i.e., hydrochloric acid
  • enzymes e.g., pepsin
  • the factors include: (1) drinking, smoking, medication as well as other factors that destroy the barrier of gastric mucous membrane by directly damaging gastric mucous membrane or stimulating gastric acid secretion; (2) infection of all kinds of microorganism and their toxins causing the damage of gastrointestinal mucous membrane; (3) immunity factors: weakened immunologic function causing a decrease in the content of secretory IgA in gastrointestinal fluid that impairs the body discharging of bacteria and toxin, further damaging the gastrointestinal mucous membrane; (4) the regurgitation of duodenum which removes mucus on the surface of the gastric mucous membrane, thereby destroying the barrier of gastric mucous membrane; (5) chronic gastritis, leading to gastric ulcer; (6) constipation, which causes or contributes to gastrointestinal diseases; and (7) damage of intestinal wall nerves' structure due to intestinal diseases thereby resulting in constipation, etc.
  • Erosive gastritis usually is associated with serious illness or with various drugs. Stress, ethanol, bile, and nonsteroidal anti-inflammatory drugs disrupt the gastric mucosal barrier, making it vulnerable to normal gastric secretions. Infection with Helicobacter pylori, a short, spiral-shaped, microaerophilic gram- negative bacillus, is widely believed to be the leading cause of peptic ulcer diseases. H. pylori colonize the deep layers of the mucosal gel that coats the gastric mucosa and presumably disrupt its protective properties. H. pylori is thought to infect virtually all patients with chronic active gastritis.
  • antacids neutralize gastric acid by using antacids to relieve symptoms of gastritis.
  • antacids For example, aluminum and magnesium hydroxide (MAALUX® and MYLANTA®) neutralize gastric acidity, resulting in increase in p ⁇ in the stomach and duodenal bulb.
  • Aluminum ions inhibit smooth muscle contraction, thus inhibiting gastric emptying.
  • Aluminum and magnesium antacid mixtures are used to avoid bowel function changes.
  • H2- receptor antagonists include cimetidine (TAGAMET®), nizatidine (AXID®), ranitidine hydrochloride (ZANTAC®) lansoprazole (PREVACID®), and rabeprazole (ACIPHEX®).
  • Cimitidine inhibits histamine at H2 receptors of the gastric parietal cells, resulting in reduced gastric acid secretion, gastric volume, and reduced hydrogen concentrations.
  • Nizatidine competitively inhibits histamine at H2 receptors of gastric parietal cells, also resulting reduced gastric acid secretion, gastric volume, and reduced hydrogen concentrations.
  • Lansoprazole decreases gastric acid secretion by inhibiting the parietal cell H + /K + ATP pump, and is to relieve symptoms of active duodenal ulcers and erosive esophagitis.
  • Rabeprazole also decreases gastric acid secretion by inhibiting the parietal cell HNK + ATP pump, and is used for short-term treatment and symptomatic relief of gastritis, and for the treatment of active duodenal ulcers, and all grades of erosive esophagitis.
  • compositions and methods are provided for repairing and promoting regeneration of mucosa in the Gl tract in order to restore physiological structure and function to the damaged or dysfunctional mucosa, to enhance the body's ability to absorb nutrients, to achieve healthy and balanced metabolism, and ultimately to promote the general health of the whole body.
  • the compositions may be adapted for use in the treatment of dysfunctional mucosa of other organs, such as nasal, lung, anal, vaginal, aural, eye, and oral mucosa, as well as for tissue repair and regeneration of other organs such as heart, liver, pancreas, kidney, and lung.
  • a composition suitable for oral administration for promoting mucosal cell growth in the Gl tract.
  • the composition is in an oral dosage form and comprises: an edible oil homogenized with an edible wax at a concentration ranging from 0.5 % to 50% by weight and a sterol compound at a concentration of at least 0.1% by weight.
  • the concentration of the sterol compound preferably ranges from about 0.5% to 20%) by weight, more preferably about 1% to 10% by weight, and most preferably about 2% to 6% by weight.
  • the concentration of the edible wax preferably ranges from about 3% to 30% by weight, more preferably about 5% to 20% by weight, and most preferably about 6% to 10% by weight.
  • the edible wax may be any natural or synthetic wax suitable for oral administration to a human.
  • examples of edible wax include, but are not limited to, beeswax, castorwax, glycowax, and carnaubawax.
  • the edible wax is beeswax.
  • the edible oil may be any natural or synthetic oil suitable for oral administration to a human, preferably fatty acid-containing oil and excluding mineral oil.
  • natural oil include, but are not limited to corn oil, wheat germ oil, soy bean oil, rice bran oil, rapeseed oil, sesame oil, fish oil and other vegetable and animal oils.
  • the edible oil is sesame oil.
  • the composition may further comprise propolis at a concentration ranging from about 0.1 %) to 30%o by weight, more preferably from about 1%> to 20%> by weight, and most preferably from about 5%> to 10%> by weight.
  • the composition preferably contains minimum amount of water, more preferably containing less than 0.5%> of water by weight, and most preferably containing less than 0.1%> water by weight.
  • the inventive composition can be formulated readily by combining with pharmaceutically acceptable carriers that are well known in the art.
  • Such carriers enable the compounds to be formulated as tablets, pills, dragees, capsules, emulsions, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • the inventive composition is contained in capsules.
  • Capsules suitable for oral administration include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. More preferably, the inventive composition is contained in soft capsules.
  • the inventive composition may be dissolved or suspended in suitable liquids, such as fatty oils or liquid polyethylene glycols. In addition, stabilizers may be added.
  • a composition suitable for oral administration as a pharmaceutical or nutraceutical comprises: an active ingredient; and an edible oil homogenized with an edible wax at a concentration ranging from 3%> to 30 %> by weight, wherein the edible wax forms microcrystals which are dispersed substantially uniformly in the edible oil at ambient temperature.
  • the size of the microcrystal is preferably between 0.1-100 ⁇ m, more preferably 5-70 ⁇ m, and most preferably 10-50 ⁇ m in length.
  • the form of the microcrystals may vary depending on the concentration and temperature. At ambient temperature, the microcrystal may adopt a single, needle-like crystal form and/or form a microcrystal complex by aggregating with each other.
  • the composition may further comprise a sterol compound at a concentration ranging from 0.1%> to 20%> by weight, more preferably about 1%> to 10%) by weight, and most preferably about 2%> to 6% by weight.
  • the active ingredient may be any drug for treating diseases or to promote general health, such as drugs in the class of 1) gastrointestinal agents; 2) antibiotics; 3) antiviral agents; 4) antifungal agents 5) antineoplastic agents; 6) analgesics; 7) tranquilizers; 8) narcotic antagonists; 9) antidepressants; 10) antihistamines; 11) antimigraine; 12) cardiovascular drugs; 13) calcium channel blockers; 14) appetite suppressant; 15) contraceptive agents; 16) corticosteroids; 17) local anaesthetics; 18) diuretics; 19) antihypertensive agents; 20) steroids; 21) prostaglandins; 22) anti- inflammatory drugs; 23) antithrombotic agents; 24) cardiac glycosides; 25) antiparkinso
  • the sterol compound may be an animal sterol or a plant sterol (also called phytosterol).
  • the sterol compound may be esterified by the fatty acid in the oil in the composition under suitable conditions such as high temperature (e.g., > 100 °C).
  • animal sterol examples include cholesterol and all natural or synthesized, isomeric forms and derivatives thereof.
  • the sterol compound is selected from the group consisting of stigmasterol, campesterol, ⁇ -sitosterol, chalino sterol, clionasterol, brassicasterol, ⁇ -spinasterol, dancosterol, desmosterol, poriferasterol, and all natural or synthesized, isomeric forms and derivatives thereof. More preferably, the sterol compound is a combination of stigmasterol, ⁇ -sitosterol,and campesterol, collectively referred to herein as "sitosterol".
  • the inventive composition may further comprise baicalin, preferably at a concentration ranging from about 0.01 to 5% by weight, more preferably about 0.1 to 2%> by weight, and most preferably about 0.1 % to 1 % by weight.
  • the inventive composition may further comprise an extract of huangqin (Radix Scutellariae) in aqueous solution, organic solvent such as oil and alcohol, or in a combination of water and organic solvent.
  • the edible oil in the composition is an extract of huangqin in the amount of 1-50% by weight in the oil.
  • the root of huangqin is used and may be obtained from the plant selected from one or more members of the group of Scutellaria viscidula Bge, Scutellaria amoena C. H. Wright, Scutellaria rehderiana Diels, Scutellaria ikonnikovii Juz, Scutellaria likiangensis Diels and Scutellaria hypericifolia Levl of Labiatae Family.
  • the inventive composition may further comprise obaculactone, preferably at a concentration ranging from about 0.01 to 5%o by weight, more preferably about 0.1 to 2% by weight, and most preferably about 0.1%> to 1%> by weight.
  • the inventive composition may further comprise an extract of dry huangbai (Phellodendron amurense Rupr), in aqueous solution, organic solvent such as oil and alcohol, or in a combination of water and organic solvent.
  • the edible oil in the composition is an extract of huangbai in the amount of 1-50% by weight in the oil.
  • the bark of huangbai is used and may be obtained from the plant selected from one or more members of the group of Phellodendron chinense Schneid, Plellodendron chinense Scheid var. glabriusculum Schneid, Phellodendron chinense Schneid var. omeiense Huang, Phellodendron Schneid var. yunnanense Huang and Phellodendron chinense Schneid var. falcutum Huang.
  • the inventive composition may further comprise obabenine, preferably at a concentration ranging from about
  • the inventive composition may further comprise an extract of huanglian (coptis chinensis Franch), in aqueous solution, organic solvent such as oil and alcohol, or in a combination of water and organic solvent.
  • huanglian coptis chinensis Franch
  • the edible oil in the composition is an extract of huanglian in the amount of 1-50%) by weight in the oil.
  • Root of huanglian is preferably used.
  • Huanglian may be selected from one or more members of the group of Coptis deltoidea C. Y. Cheng et Hsiao, Coptis omeiensis (Chen) C. Y.
  • the inventive composition may further comprise berberine, preferably at a concentration ranging from about 0.001%> to 2% by weight, more preferably about 0.002%> to 0.5 %> by weight, and most preferably about 0.003% to 0.1% by weight.
  • the inventive composition may further comprise narcotoline, preferably at a concentration ranging from about
  • the inventive composition may further comprise an extract of puppy capsule (Papaver somniferam L.), in aqueous solution, organic solvent such as oil and alcohol, or in a combination of water and organic solvent.
  • the edible oil in the composition is an extract of puppy capsule in the amount of 1-20% by weight in the oil.
  • the inventive composition may further comprise an extract of huangqin, huangbai and huanglian in aqueous solution, organic solvent such as oil and alcohol, or in a combination of water and organic solvent.
  • organic solvent such as oil and alcohol
  • the edible oil in the composition is an extract of a combination of huangqin, huangbai and huanglian, the total amount of the combination being 1-50% by weight in the oil.
  • the inventive composition may further comprise an extract of huangqin, huangbai, huanglian, and poppy capsule in aqueous solution, organic solvent such as oil and alcohol, or in a combination of water and organic solvent.
  • the edible oil in the composition is an extract of a combination of huangqin, huangbai, huanglian and poppy capsule, the total amount of the combination being l-50%o by weight in the oil.
  • the inventive composition may further comprise various amino acids, preferably all 18 natural amino acids, for providing nutrition support to cell growth. The amino acids may be chemically synthesized or obtained from natural sources.
  • the inventive composition may further comprise an extract of earthworms in aqueous solution, organic solvent such as oil and alcohol, or in a combination of water and organic solvent.
  • organic solvent such as oil and alcohol
  • the edible oil in the composition is an extract of earthworms that is in the amount of 1- 50%) by weight in the oil.
  • the inventive composition may further comprise an extract of huangqin, huangbai, huanglian, poppy capsule, and earthworms in aqueous solution, organic solvent such as oil and alcohol, or in a combination of water and organic solvent.
  • the edible oil in the composition is an extract of a combination of huangqin, huangbai, huanglian, poppy capsule, and earthworms, the total amount of the combination being 1-50% by weight in the oil.
  • the present invention provides methods for protecting and repairing mucosa, presumably by promoting the growth of regenerative mucosal cells. By using these methods, physiological structure and function of the damaged or dysfunctional mucosa may be restored to enhance the body's ability to absorb nutrients, which, in turn, can improve the body's general health and strength the immune system to fight diseases.
  • a method for preventing ulceration or irritation of mucosa in the gastrointestinal tract of a host.
  • the method comprises: orally administering to the host a composition comprising an edible oil homogenized with an edible wax at a concentration ranging from 0.5 %> to 50%) by weight and a sterol compound at a concentration of at least 0.1% by weight.
  • the host is preferably a human.
  • the composition may be administered to the host prior to consumption of alcohol, spicy food or other irritants to the stomach.
  • the composition may be administered to the host post consumption of these irritants to the stomach.
  • a method of treating a host having a gastrointestinal disorder is provided.
  • the method comprises: orally administering to a host having a gastrointestinal disorder a composition comprising an edible oil homogenized with an edible wax at a concentration ranging from 0.5 %> to 50%> by weight and a sterol compound at a concentration of at least 0.1%) by weight.
  • the host is preferably a human.
  • the composition may be used as a pharmaceutical, a nutraceutical or a health food with or without a physician's prescription.
  • the dosing regimen may vary depending on the severity of the condition of the host.
  • the composition is preferably administered in an amount of 0.5-10 g per day, more preferably 2-8 g per day, and most preferably 3-6 g per day. For example, if the composition is supplied as 0.5 g soft gel capsules, 1-10 capsules may be administered twice a day.
  • gastrointestinal disorders include, but are not limited to, gastrointestinal diseases, such as acute gastritis, chronic superficial gastritis, atrophic gastritis, antral gastritis, senile gastritis, bile-regurgitational gastritis, esophagitis, gastroduodenal ulcer, indigestion, gastric neurosis, constipation, as well as various consequent conditions including gastric hyperacidity, hypochlorhydria, flatulency, gastrointestinal discomfort after meals, gastric discomfort after drinking, and gastric discomfort due to fasting.
  • a method is provided for treating a patient having a gastrointestinal cancer.
  • the method comprises: orally administering to a patient having a gastrointestinal cancer a composition comprising an edible oil homogenized with an edible wax at a concentration ranging from 0.5 % to 50%> by weight and a sterol compound at a concentration of at least 0. ⁇ % by weight.
  • the gastrointestinal (Gl) cancer can be an upper or lower Gl cancer.
  • the upper Gl cancer examples include, but are not limited to, 1) esophagus cancer; 2) stomach cancer; 3) pancreas cancer; 4) liver cancer; and 5) cancer of bile ducts.
  • the lower Gl cancer examples include, but are not limited to, cancers of the large bowel such as colorectal carcinoma, primary lymphomas, melanoma, and sarcoma of the large bowel.
  • the inventive composition may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials Various types have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the inventive compositions for a few weeks up to over 100 days.
  • a method for manufacturing a composition for delivering active ingredients to a mucosal tissue in vivo comprises: heating an edible wax at a temperature above its melting point; heating an edible oil at a temperature above the melting point of the edible wax; mixing the melted wax with the oil at a weight ratio ranging from 3:97 to 20:80; and homogenizing the mixture of the wax and oil.
  • the method may further comprise: adding the root of Radix Scutellaria to the edible oil at a weight ratio ranging from 1:99 to 10:90 and heating the mixture at a temperature above the melting point of the edible wax.
  • the method may further comprise: adding the homogenized mixture of the wax and oil into a gel capsule.
  • the gel capsule may be a hard or a soft gel capsule.
  • the edible wax is preferably beeswax with a melting point of 70-80°C and the edible oil is sesame oil.
  • the mixture of the wax and oil may be homogenized on a homogenizer, preferably at a speed of 6000 -10000 rpm at 35-45°C for 15-20 min.
  • the mixture of the wax and oil may be homogenized on a colloid mill.
  • a method is provided for manufacturing a composition for protecting or treating damaged mocosal tissue in vivo.
  • the method comprises: heating a mixture of sesame oil and huangqin at a weight ratio between 70:30 and 98:2 at a temperature between 80-180 °C for 10-120 min; filtering the mixture to obtain a sesame oil filtrate; cooling the sesame oil filtrate to between 70- 90 °C; adding beeswax to the sesame oil filtrate at a weight ratio between 3:93- 10:90; heating the mixture of beeswax and the sesame oil filtrate with stirring at a temperature between 80-180 °C for 10-60 min; and homogenizing the mixture of beeswax and the sesame oil filtrate.
  • a method for manufacturing a composition for protecting or treating damaged mocosal tissue in vivo comprises: heating a mixture of sesame oil and a combination of dry huangqin, huangbai, huanglian, poppy capsule and earthworm at a temperature between 80- 180°C for 10-120 min, the weight ratio between the sesame oil and the combination being between 70:30 and 98:2; filtering the mixture to obtain a sesame oil filtrate; cooling the sesame oil filtrate to between 70-90 °C; adding beeswax to the sesame oil filtrate at a weight ratio between 3:93-10:90; heating the mixture of beeswax and the sesame oil filtrate with stirring at a temperature between 80-180 °C for 10-60 min; and homogenizing the mixture of the mixture of beeswax and the sesame oil filtrate.
  • homogenizing the mixture of beeswax and the sesame oil filtrate may include homogenizing the mixture until particles or microcrystals of beeswax are substantially uniformly dispersed in the oil at ambient temperature.
  • Figure 1 illustrates the fundamental principle of adult tissue repair and organ regeneration according to the present invention.
  • Figure 2 depicts specific techniques used for cultivating adult regenerative stem cells and for promoting physiological tissue repair and functional organ regeneration.
  • Figure 3A shows the stomach of a rat suffered from severe ulcer after ingesting anhydrous alcohol.
  • Figure 3B shows the stomach of a rat that suffered from severe ulcer after ingesting anhydrous alcohol and was treated with the content of Gl Capsules daily at 0.8 g/Kg for 3 weeks.
  • Figure 4A shows a model for a pigeonhole structure adopted by beeswax when mixed sesame oil without homogenization.
  • Figure 4B shows an eletrograph of beeswax when mixed sesame oil without homogenization.
  • Figure 5 A shows a micrograph of beeswax when homogenized with sesame oil, showing single, needle-like microcrystals of beeswax.
  • Figure 5B shows a micrograph of beeswax when homogenized with sesame oil, showing microcrystal complexes of beeswax.
  • Figure 6 depicts a manufacturing process for one embodiment of the inventive composition.
  • Figures 7A-H shows micrographs of the culture of mouse intestinal tissue on day 24, 30, 38, 42, 50, 85, 90, and 97 of culturing, respectively.
  • the left panel is the control group; and the right panel the treatment group.
  • Figures 8A-H shows micrographs of the culture of mouse intestinal tissue on day 24, 30, 38, 42, 50, 70, 85, and 90 of culturing, respectively.
  • the left panel is the control group; and the right panel the treatment group.
  • the present invention provides innovative methods and compositions for physiological repair and functional regeneration of mucosal tissues of the body, in particular, mucosa in the gastrointestinal (Gl) tract.
  • the technological innovation is multi- facet in both the conceptual and practical aspects, with a primary focus on the techniques for tissue repair and organ regeneration through induction and propagation of regenerative stem cells in situ and in vivo.
  • the inventive composition was able to sustain and stimulate strong growth of mucosal cells in vitro and to promote physiological healing of gastric ulcer in animal models.
  • the inventor believes that the inventive composition can effectively repair the damaged mucosa by providing regenerative conditions in the Gl tract, especially in the stomach.
  • the inventive composition Upon administration to the Gl tract, the inventive composition is mixed with mucus of the stomach and adheres to the mucosa to form a protective membrane.
  • Such an artificial membrane protects the mucosa from further irritation of acid, alcohol, food and other material contained in the stomach. Under these conditions active ingredients in the composition are slowly released to the site to activate the regenerative stem cells there to promote fast repair of the mucosa.
  • the mucosa can be repaired and/or regenerated with a restoration of its physiological structure and function.
  • the inventive composition successfully cured gastric ulcer in animal models whereas the rats in the control group without the treatment still suffer severe gastric ulcer (Figure 3A).
  • the inventive composition may also effectively inhibit the toxicity of the bacteria H. pylori by changing its morphology. With the regeneration of a healthy Gl tract, the ulcerous conditions that are favorable for the habitation of H. pylori are destroyed, thereby indirectly inhibiting the growth of the bacteria.
  • the restoration of normal physiological structure and function to the damaged or dysfunctional mucosa the body's ability to absorb nutrients is enhanced, which, in turn, leads to a healthy and balanced metabolism and general health of the whole body.
  • the present invention discloses a completely different approach under the guidance of the following fundamental principle.
  • the present invention reveals the fundamental principle of adult tissue repair and regeneration in vivo and in situ, which is illustrated in Figure 1.
  • these nascent stem cells are quite fragile and are prone to death caused by cytotoxic effects exerted by various environmental elements, and by uncontrolled cellular responses to injury.
  • these adult stem cells proliferate and develop into various multipotent tissue stem cells by following the directions which are already genetically programmed at the embryonic development stages. Generation of such a multiple functional tissue stem cell assures ample supply of various types of cells that are needed for forming a physiologically functional tissue.
  • tissue stem cells proliferate and differentiate into specific types of cells for particular kinds of tissues.
  • tissue-specific cell adhesion associates with each other through tissue-specific cell adhesion and form a nascent tissue.
  • tissue conjunction a mode of tissue-specific cell association
  • tissue constitution Such a mode of organ specific tissue association in an adult is collectively referred to herein as "tissue constitution”.
  • the nascent tissues within the reconstituted organ develop and mature into individual, functional tissues with physiologically balanced cell types and numbers under the regulation of the inventive composition. Meanwhile, these tissues undergo further remodeling through communications of tissues within the network of the live organ and eventually form a fully functional, mature organ (Figure 1).
  • ulcerous gastric tissue could be repaired with the inventive methodology.
  • the inventor believes that by in situ cultivation of regenerative stem cells within a live body under an optimum developmental condition, the damaged organ can be regenerated with a complete restoration of its physiological structures and functions. This regeneration process takes place spontaneously within the body under the regulation of both endogenous and exogenous materials provided in the present invention. Ultimately, successful organ regeneration depends on physiologically proper tissue-specific multi-cell adhesion, organic-specific multi- tissue assembly, and homeostatically balanced and immunologically compatible coexistence of multi-organs within a live body.
  • stem cells 1) Redefinition of "stem cells" Based on this fundamental principle and its successful application in organ regeneration in the clinic, the meaning of a stem cell is redefined in the present invention.
  • a classic definition of a stem cell is that a stem cell should have the following properties: 1) It is not itself terminally differentiated, i.e., not at the end of a pathway of diffentiation; 2) It can divide without limit or at least for the life time of the animal; and 3) When it divides, each daughter cell can either remain a stem cell, or embark on a course leading irreversibly to terminal differentiation.
  • Molecular Biology of the Cell Alberts et al., eds, 3 rd ed. (1994), pp. 1155-1156, Garland Publishing Inc., New York and London.
  • stem cells isolated from human tissue such as the embryonic stem cells isolated from the inner cell mass of human blastocysts, are still stem cells even if they are completely isolated from a live human body and reside in culture medium in vitro.
  • stem cells although capable of divide without limit and differentiate into cells of various tissue types, have not been shown to be able to regenerate a fully functional human organ, not even mentioning a live human in vitro.
  • the stem cell according to the present invention is termed as a "regenerative stem cell”.
  • This regenerative cell has the following characteristics: 1) it resides in a live body; 2) it is under the physiological control and regulation of the body; 3) it coexists with the tissues and organs of the body, 4) it is capable of continuous cell division within the live body; 5) it is capable of repairing tissues, regenerating organs, and restoring physiological structures and functions to the regenerated organs.
  • Tissues with high rates of cell turnover such as blood and epithelia
  • Other Tissues such as liver, bone, muscle, blood vessels, and adrenal cortex regenerate in response to injure.
  • the liver regenerates by compensatory hyperplasia
  • other tissues regenerate by the activation of reserve stem or progenitor cells perhaps by augmenting the regeneration of mesenchymally-derived tissues, or within the regenerating tissue.
  • hematopoietic cells such as T cells, B cells, neurotrophil, and erythrocytes are regenerated from hematopoietic stem cells in the bone marrow.
  • Finger tips will regenerate if amputated distal to the terminal phalangeal joint.
  • neither bone nor muscle will regenerate across a gap, and other organs as skin, pancreas, heart, and spinal cord respond to injury by the formation of scar tissue.
  • the distinct, novel approach disclosed in the present invention focuses on harnessing the body's inherent ability to repair and regenerate itself. Under optimum physiological conditions, such as bathing in the warm, sterile amniotic fluid, a fetus could heal its wound spontaneously without scar and loss of function. Unfortunately, a fully developed human is exposed to a completely different, more hostile environment. Under the influence of both endogenous and exogenous conditions, spontaneous adult wound healing and organ generation go tlirough somewhat different pathways and end up with scars and dysfunction of organs. This spontaneous healing process is totally passive, uncontrolled by therapeutic interventions by embarking on a course of chaotic cell proliferation and differentiation and reconstitution of regenerated tissues. In addition, mucosa of the Gl system, which is constantly exposed to harsh, acidic environment, once damaged, may not be able to repair itself without therapeutic intervention.
  • the present invention provides methods and compositions to actively control the whole process of tissue repair and organ regeneration.
  • cells the smallest unit of life, are stimulated, propagate, differentiate, integrate with each other to physiologically repair the damaged tissues or to regenerate the tissue destroyed in various courses, such as trauma and diseases.
  • These nascent tissues then conjoin together to form a fully functional organ. To achieve this result in an adult, specific, active human intervention is needed.
  • the general guidance for this intervention revealed in the present invention is that 1) for injured or damaged tissues, the viable cells in the remaining tissues should be preserved to a maximum extent; 2) necrotic cells or tissues should be removed as early as possible; 3) the regenerative cells should be activated and propagated in an environment mimicking the their own native physiological conditions; and 4) regulators for cell growth and differentiation are administered to the regenerating organ to direct proper, physiological repair of tissues.
  • ASCs adult stem cells
  • Multipotent adult stem cells are produced in vivo and in situ by a) activating dormant tissue stem cells such as epithelial stem cells putatively residing in the bulge of a hair follicle, and or b) inducing dedifferentiation of fully dedifferentiated cells and converting them into ASCs.
  • dormant tissue stem cells such as epithelial stem cells putatively residing in the bulge of a hair follicle, and or b) inducing dedifferentiation of fully dedifferentiated cells and converting them into ASCs.
  • the fragile, nascent ASCs are cultured in a physiologically moist environment to allow rapid growth and directionally differentiation;
  • Necrotic tissues of the mucosa are removed by adhering to the inventive composition and exudate from the wound automatically, thus greatly reducing the risk of physical or chemical injury to residual viable tissue;
  • ASCs and their differentiated cells are cultured in an exogenous culture medium provided by the present invention to allow rapid cell growth, integration and migration to physiologically repair the damaged tissue or regenerate lost tissue;
  • Toxicity of bacteria infecting the wound are inhibited not by topically applying antibiotics to kill the bacterial cells, rather by allowing a bacterial cell to replicate genetically and change its morphology under a condition provided by an inventive composition, leading to reduced production of toxin; and thus greatly reduce inflammation caused by the body's immune response to bacterial toxin.
  • the inventive composition By adhering to the mucosa in the stomach, for example, the inventive composition provides a moist and yet less acidic environment favorable for the growth of regenerative epithelial stem cells for the repair of ulcerous mucosa.
  • Oral administration of an inventive composition to the Gl tract results in formation of an artificial membrane by adhering to the mucosa.
  • This membrane isolates the damaged mucosa from the exterior harsh environment and yet allows slow, sustained release of active ingredient and nutrients to the tissues beneath.
  • mucosa and its underlying tissues can be regenerated, which, in turn, leads to restoration of normal functions of the organs in the Gl tract, such as nutrient uptake and metabolism.
  • Oxygen required for cell growth can permeate through this membrane to reach the tissues beneath. Meanwhile, bacteria and other environmental contaminates are separated from the tissues undergoing repair and regeneration.
  • organ transplantation and implantation of bionic device Clinical approaches current available to replace failing organs and tissues are organ transplantation and implantation of bionic device.
  • organ transplantation are donor shortages and immunosuppressive side effects.
  • the drawback to the approach of implantation of bionic device is the inability to manufacture artificial materials that duplicate the durability, strength, form, function, and biocompatibility of natural tissues.
  • Transplantation of cells involves ex vivo culturing and propagation of stem cells and then transplant them or their differentiated products to the site where the damaged organ resides.
  • progress in biology has made it possible for apply the cell transplantation in the clinic, multiple practical limitations still exist and the clinical results are not physiological or cosmetically satisfactory.
  • One of the limitations associated with this approach is the difficulties with identification and isolation of multipotent stem cells from various tissues.
  • pluriopotent human embryonic stem cell (ESC) lines have been cultured recently, directional differentiation of the ESCs remains a mystery.
  • mice neuronal and glial cells derived from neural stem cells in vitro, and cardiomyocytes derived from ESCs in vitro integrate into the surrounding tissue when injected into an adult brain and heart, respectively.
  • Multipotent human neural stem cells injected into the developing brain of mouse embryos migrate throughout the brain and differentiate site-specifically.
  • Stem cells cultured in vitro must be directed to differentiate into site-specific phenotypes once they are transplanted into the lesion site. Complete deciphering of the signal needed for this process is required to guide the design of the in vitro tissue culturing conditions.
  • Experimental data obtained by others in the art show that although multipotent human mesenchymal, mouse neural stem cells, and mouse embryonic stem cells can be grown in vitro through the addition of leukemia inhibitory factor (LIF) to the culture medium, mouse ESCs differentiate randomly in vitro and in vivo.
  • LIF leukemia inhibitory factor
  • Immuno-rejection of the transplant is another major problem associated with cell transplantation. While autogeneic cells can be used in some instances (e.g., mesenchymal stem cells from bone marrow), most transplanted cells will be allogeneic. Attempts have been made to use genetic modification and cell biological strategies to promote host tolerance of allogeneic or xenogeneic transplants, such as fusing diploid somatic cells to an enucleated human or other mammalian egg and using the resultant blastocyst to make the stem cells. Such approaches trigger bioethical concerns, a problem even harder to solve. Implantation of bioartificial tissues constructed in vitro also faces a few obstacles.
  • scaffolding material for bionic implants that have the requisite topography, surface properties, and growth and differentiative signals to facilitate cell migration, adhesion, proliferation and differentiation, as well as being moldable into the shape of various tissues and organs.
  • artificial biomaterials currently being used or tested include various ceramics, polyurethane elastomers, polyesters, polyanhydrides, and polyphosphazenes. These materials provide mechanical support, migration channels, and adhesive surfaces for cells.
  • the present invention provides an innovative methodology for adult tissue repair and organ regeneration.
  • the methodology is focused on the activation and cultivation of adult stem cells in vivo and in situ.
  • the methodology has developed to provide optimum conditions for the body's spontaneous regeneration, a regenerative environment mimicking that needed for healthy fetal development.
  • Inventive compositions are provided to activate dormant stem cells to proliferate or to induce conversion of adult tissue cells into regenerative stem cells, and to maintain active proliferation and directional differentiation of these stem cells into all cells needed for regeneration in vivo and in situ.
  • Novel formulation of the active ingredients also facilitates a physiologically moist, nutritious, homeostatically balanced environment to ensure repair and regeneration of tissues and organs with complete restoration of their physiological structures and functions.
  • compositions are developed as pharmaceuticals or nutraceuticals for maintaining normal functions or repairing damaged mucosa and other tissues in the Gl tract.
  • tissue cells in any organ of a human body can be activated to produce regenerative stem cells in response to signals of tissue repair, e.g., wounds and ulcer, as long as proper regenerative conditions are provided.
  • tissue repair and functional organ regeneration in a fully developed adult is achievable only by providing an exogeneous culture media in vivo and in situ to stimulate and maintain rapid proliferation and directional differentiation of the adult stem cells and to ensure proper assembly of various tissues organ-specif ⁇ cally without substantial loss in their structures and functions.
  • ASCs adult stems cells
  • Figure 1 The inventor believes that although difficult to be labeled and isolated, multipotent, adult stems cells (ASCs) can be produced in vivo and in situ by activating dormant tissue stem cells and/or by inducing conversion of adult tissue cells into ASCs ( Figure 1). This belief is supported by recent advances in stem cell research and by the experimental and clinical data generated in the application of the fundamental principle elucidated in the present invention. ASCs have been discovered recently in the liver, pancreas, and central nervous system. Mesenchymal stem cells have been isolated from the bone marrow, and there is some evidence that similar cells may even reside in the connective tissue compartments of tissues throughout the body. The locations of ASCs have been searched extensively and speculated by others to be residing in specific niches.
  • the methods and compositions provided by the present invention can be used to activate ACSs in the body to repair damaged tissues and to regenerate dysfunctional organ in situ and in vivo. It is envisioned that this innovative methodology can be used for restoring the physiological structure and function of any tissue and any organ of the body of a mammal, preferably a human. The following section lays out the applications in the prevention and treatment of disorders in the Gl tract.
  • the methodology of the present invention can be used to activate or induce regenerative stem cells in tissues in the Gl tract so as to repair diseased or damaged mucosa of the organs in the tract.
  • each crypt is composed of about 250 epithelial cells among which epithelial stem cells are included. These multipotent stem cells are located near or at the base of each crypt. Loeffler et al. (1993) J. Theor. Biol. 160:471-491.
  • the intestinal epithelial stem cells response to mesenchymal cues for survive and differentiation. Normally, these cells are slowly recycling, much like the hair follicle stem cells. Some of them are converted to rapidly but transiently proliferating cells that move to the midsegment and subsequently differentiate into either the absorptive brush-border entercytes, mucus-secreting goblet cells, or enteroendocrine cells of the villi. To maintain homeostasis, the differentiated cells then die and are shed from the villi into the lumen of the gut. As the body ages, the growth potential of intestinal epithelial stem cells is weakened; and it becomes more difficult to activate the stem cells.
  • the present invention provides compositions and methods that can be used to enhance nutrient uptake of a mammal, especially a human.
  • the inventive compositions are highly adhesive to mucosa and can be used to deliver various nutrients and/or active ingredient(s) to stimulate ASCs for tissue repair and regeneration.
  • the composition adheres to the mucosa in the Gl tract and protects the mucosa from irritation caused by consumption of alcohol, spicy food, etc.
  • inventive compositions can be used as nutrient supplements or nutraceuticals for a healthy person to protect the mucosa and prevent the onset of various disorders associated with damaged or weakened mucosa.
  • active ingredients for stimulating regeneration of the body can be delivered in a sustained-release manner to provide constant and adequate nutrients to support and stimulate the growth of mucosal and other types of tissue cells in situ and in vivo.
  • the inventive composition of the present invention can also be used for treating digestive disorders in a human patient.
  • Digestive disorders may be a condition of a human as a result of disorders of and damage to the organs of the digestive tract or the alimentary canal, including the mouth, esophagus, stomach, and large and small intestine.
  • Disorders of the digestive tract include peptic ulcer diseases, inflammatory bowel diseases and other insults.
  • H. pylori Helicobacter pylori
  • Infection of H. pylori leads to active, chronic gastritis and frequently to associated syndromes such as duodenal ulcer, gastric ulcer, gastric cancer, MALT lymphoma, or Menetrier's syndrome. Eradication or inhibition of H. pylori should reduce the recurrence of duodenal and gastric ulcers.
  • IM intestinal metaplasia
  • the inventive composition can effectively repair the damaged mucosa by providing regenerative condition in the Gl tract, especially in the stomach.
  • the inventive composition Upon administration to the Gl tract, the inventive composition is mixed with mucus of the stomach and forms a protective membrane containing mucin, separating the mucosa from further irritation of acid, alcohol, food and other materials contained in the stomach. Under these conditions the sterol compound and other optional active ingredients in the composition are released to the site and activate the regenerative stem cells there to promote fast healing of the mucosa.
  • the inventive composition successfully cured gastric ulcer in animal models. Further, the inventive composition may also effectively inhibit the toxicity of the bacteria H. pylori by changing its morphology.
  • the methods and composition of the present invention can be used in the treatment of H. pylori infection and conditions associated with H. pylori infection (e.g., ulcers, gastric carcinoma, non-ulcer dyspepsia, gastritis, and esophageal lesions associated with gastro-esophageal reflux disease).
  • the inventive composition is useful for treatment of these conditions because of its generally protective effect on the gastrointestinal (Gl) tract. In addition, it promotes the maintenance of mucosal integrity.
  • the inventive composition of the present invention can be used to inhibit adhesion to or colonization of the mucosa by H pylori. It may also be used promote healing of tissues damaged by conditions associated with H. pylori infection. In this regard, it is presumed that addition of the inventive composition to wounded monolayers of confluent intestinal epithelial cells activates epithelial stem cells in the crypts and increases the rate of epithelial cell migration into the wound.
  • the inventive composition can be used to protect other parts of the gastro-intestinal tract or alimentary canal, such as the intestine, it can be used to protect the mouth and esophagus from damage caused by radiation therapy or chemotherapy.
  • Radiation and systemic administration of anticancer drugs have cytotoxic effects on fast proliferative cells such as lymphocytes, mucosal cells and hair cells, leading to myelosuppression, mucositis, and alopecia, respectively.
  • These side effects of anticancer therapy not only significantly lower the patient's quality of life but also cause a lot of pain and suffering in the patient and his/her family.
  • damages to the mucosa result in a poor uptake of nutrients which are needed for boosting the body's immune system to fight the cancer.
  • the inventive composition of the present invention the damaged mucosa may be repaired and its physiological functions be restored, thereby indirectly inhibiting the growth and metastasis of cancer.
  • the methodology and inventive compositions of the present invention may be used for treating or preventing hyperproliferative diseases or pre-cancerous conditions affecting epithelial cells of the internal organs, such as organs in the gastrointestinal (Gl) tract.
  • Administration of the inventive composition orally may restore the homeostatic balance of these organs by reestablishing the cell-cell cross-talk between the precancerous cells with the healthy cells of the host.
  • Cancer is generally viewed as the result of disrupted intra- and intercellular homeostatic regulation. Once the homeostatic balance is lost and malignant transformation has occurred, microenvironment factors such as degradation of matrix components and host-tumor interactions are essential for survival and growth of the malignant cells.
  • the homestatic balance of tissues may be restored without loss of physiological functions.
  • the ability of the inventive composition to promote growth of intestinal and gastric cells to form tissues in vitro indicates that the inventive composition likely is able to regulate intercellular communication and promote cell-cell interactions by stimulating cross-talk mediated by various cell membrane proteins such as connexins and cadherins. This results in a coordinated regulation of cell growth, differentiation, apoptosis and migration.
  • the inventive composition may assert its function of restoring tissue homestatic balance through promoting the formation of gap junctions between precancerous or cancer cells and the host cells.
  • Gap junctions are a unique type of intercellular junction found in most animal cell types. Two adjacent cells interact with each other through the cell membrane proteins, connexins, which form the gap junction. Six identical connexins from a connexon; two connexons join across the intercellular gap to form a continuous aqueous channel connecting the two cells.
  • Each gap junction is a cluster of homogeneous intramembrane particles associated with the cytoplasmic fracture face of the plasma membrane. Each intramembrane particle corresponds to a connexon.
  • Gap junctions permit the intercellular passage of small molecules and have been implicated in diverse biological processes, such as development, cellular metabolism, and cellular growth control.
  • connexins are modified posttranslationally by phosphorylation, primarily on serine amino acids.
  • Connexins are targeted by numerous protein kinases, ofwhich some have been identified: protein kinase C, mitogen-activated protein kinase, and the v-Src tyrosine protein kinase. Phosphorylation has been implicated in the regulation of a broad variety of connexin processes, such as the trafficking, assembly/disassembly, degradation, as well as the gating of gap junction channels.
  • cadherin also plays important role in cell-cell adhesion and migration. It has been found that cadherin-mediated cell- cell adhesion is perturbed in protein tyrosine kinase (PTK)-transformed cells. While cadherins themselves appear to be poor PTK substrates, their cytoplasmic binding partners, the Arm catenins, are excellent PTK substrates and therefore good candidates for mediating PTK-induced changes in cadherin behavior. For example, beta-catenin binds to the cytoplasmic region of classical cadherins and function to modulate adhesion and/or bridge cadherins to the actin cytoskeleton.
  • PTK protein tyrosine kinase
  • the inventive composition activates these kinases which then phosphorylate connexins and the cellular binding partners of cadherins such as catenins.
  • the communication channels between the tumor cells and the host cells are restored.
  • the tumor cells are subjected to the regulation of the host.
  • the tumor cells may be induce to undergo apoptosis (programmed cell death) or differentiate to become non-tumorigenic.
  • the methodology of the present invention is used for treating cancer in the upper and lower Gl tract.
  • Examples of upper Gl cancer include, but are not limited to, 1) esophagus cancer caused by excessive alcohol use, lye ingestion, achalasia, cigarette smoking, exposure to nitroamine, Barrett's mucosa, tylosis, mycotoxin, infection with transforming viruses such as human pappiloma virus (HPV), he ⁇ es simplex virus (HSV), cytomegalovirus (CMV) and Epson-Barr virus (EBV), Plummer Vinson Syndrome; 2) stomach cancer caused by achlorhydria, Helicobacter pylori infection, previous gastrectomy, and Billroth II procedure; 3) pancreas cancer caused by cigarette smoking, exposure to beta- naphthylamine, benzidine, and chronic pancreatis; 4) liver cancer caused by hepatitis B virus, chronic liver diseases such as chronic active hepatitis and cirrhosis, exposure to mycotoxin, ionizing radiation, steroid hormones and arsenic;
  • Examples of lower Gl cancer includes cancers of the large bowel such as colorectal carcinoma, primary lymphomas, melanoma, and sarcoma of the large bowel.
  • Adenocarcinomas account for more than 90%> of large bowel cancers.
  • Cancinoid tumors account for most of the rest of malignant neoplasma arising in the colorectum.
  • the present invention provides novel compositions for pharmaceutical or nutraceutical use in an animal, preferably in a human.
  • a pharmaceutical is a composition that is used as a medicament to cure a disease condition with or without a physician's prescription.
  • a nutraceutical is a composition that is used as a nutritional supplement for promoting general health or to remedy a particular condition of the body. Nutraceuticals are usually sold in health food stores and supplied without a physician's prescription.
  • compositions are provided for promoting cell growth, tissue repair and organ regeneration, preferably in vivo. It should be noted the compositions may be adapted for use in vitro as cell growth culture media or in ex vivo reconstruction of tissues and/or organs.
  • compositions are provided for repairing and promoting regeneration of mucosa in the Gl tract in order to restore physiological structure and function to the damaged or dysfunctional mucosa, to enhance the body's ability to absorb nutrients, to achieve healthy and balanced metabolism, and ultimately to promote the general health of the whole body.
  • the compositions may be adopted for use in the treatment of dysfunctional mucosa of other organs, such as nasal, lung, anal, vaginal, aural, eye, and oral mucosa.
  • a composition suitable for oral administration is provided for promoting mucosal cell growth in the Gl tract.
  • the composition is in an oral dosage form and comprises: an edible oil homogenized with an edible wax at a concentration ranging from 0.5 %> to 50% ⁇ by weight and a sterol compound at a concentration of at least 0.1 %> by weight.
  • the concentration of the sterol compound preferably ranges from about 0.5% to 20%) by weight, more preferably about 1%> to 10%> by weight, and most preferably about 2% to 6% by weight.
  • the concentration of the edible wax preferably ranges from about 3%> to 30% by weight, more preferably about 5%> to 20%> by weight, and most preferably about 6% to 10% by weight.
  • the sterol compound may be an animal sterol or a plant sterol (also called phytosterol).
  • the sterol compound may be esterified by the fatty acid in the oil in the composition under suitable conditions such as high temperature (e.g., >100 °C).
  • suitable conditions such as high temperature (e.g., >100 °C).
  • animal sterol include cholesterol and all natural or synthesized, isomeric forms and derivatives thereof.
  • the sterol compound is selected from the group consisting of stigmasterol, campesterol, ⁇ -sitosterol, chalinosterol, clionasterol, brassicasterol, ⁇ -spinasterol, daucosterol, desmosterol, poriferasterol, and all natural or synthesized, isomeric forms and derivatives thereof. More preferably, the sterol compound is a combination of stigmasterol, ⁇ -sitosterol, and campesterol, collectively referred to herein as "sitosterol".
  • the inventor believes that the sterol compound may play important roles in inducing mo ⁇ hogenesis of the cells by changing the fluidity and permeability of the cell membrane. As a result, many cell membrane-associated proteins such as kinases and phosphotases may be activated to stimulate cell growth. It is also plausible that dormant stem cells may be activated due to mo ⁇ hogenic changes in the membrane. Further, differentiated adult tissue cells may also be induced to undergo transformation into a non- differentiated phenotype, i.e., the process called "dedifferentiation".
  • CAMs cell adhesion molecules
  • production of prostaglandin (PG) may be stimulated by the sterol compound, which, in turn, can stimulate secretion of gastric mucus to form an effective barrier to resist irritation to the mucosa.
  • sterol compound for use in this invention may be procured from a variety of natural sources.
  • phytosterol may be obtained from the processing of plant oils (including aquatic plants) such as corn oil, wheat germ oil, soy extract, rice extract, rice bran, rapeseed oil, sesame oil, and other vegetable oils, and fish oil.
  • phytosterols may be prepared from vegetable oil sludge using solvents such as methanol.
  • phytosterols may be obtained from tall oil pitch or soap, by-products of the forestry practice.
  • the edible oil may be any natural or synthetic oil suitable for oral administration to a human. Examples of natural oil include, but are not limited to corn oil, wheat germ oil, soy bean oil, rice bran oil, rapeseed oil, sesame oil, fish oil and other vegetable and animal oils.
  • the edible wax may be any wax suitable for oral administration to a human, either natural or synthetic.
  • examples of edible wax include, but are not limited to, beeswax, castorwax, glycowax, and carnaubawax.
  • the edible wax for example beeswax, usually has a higher melting point than the edible oil (e.g., sesame oil).
  • Beeswax is solid at room temperature and melts when heated to about 70-80°C. When melted, the wax can be mixed with the oil with adequate stirring. However, when the mixture of beeswax and sesame oil is allowed to cool down to ambient temperature (i.e., 20-25°C), beeswax cools down much faster than the oil due to their differential thermo-physical properties.
  • FIG. 4A illustrates a model structure with beeswax forming the pigeonholes and oil drops enclosed therein.
  • Figure 4B shows an electronograph of a mixture comprising about 10%> beeswax and about 90%> sesame oil. As shown in Figure 4B, beeswax forms a three-dimensional pigeonhole-like structure with the dimension of the holes averaged at 19 ⁇ m and has individual oil drops enclosed therein.
  • Figures 5A-B are micrographs showing the microcrystals of beeswax in an embodiment of the composition comprising about 7% of beeswax homogenized with about 92%> of sesame oil.
  • Figures 5A-B there are two major forms of the microcrystals: needle-like microcrystals (Figure 5A) and microcrystal complexes in bundles or in various asterisk shapes (Figure 5B).
  • Figure 5A needle-like microcrystals
  • Figure 5B microcrystal complexes in bundles or in various asterisk shapes
  • microcrystals of beeswax are dispersed in the oil quite uniformly without forming a connected 3D network structure.
  • the size of the needle-like microcrystal varies from small (e.g., 7 ⁇ m in length and 0.4 ⁇ m in width), medium (e.g., 28 ⁇ m in length and 0.6 ⁇ m in width), to large (e.g., 52 ⁇ m in length and 0.8 ⁇ m in width).
  • the size of the microcrystal complexes varies from small (e.g., 18 ⁇ m in diameter), medium (e.g., 36 ⁇ m in diameter), to large (e.g., 50 ⁇ m in diameter).
  • this unique feature of the composition formed by homogenizing the wax and the oil confers a superior ability to the composition to adhere to mucosa and a much higher efficacy in the treatment of acute ulcer caused by alcohol in animal models.
  • seven rats in the control group to which only water was given developed ulcer after being gavaged with anhydrous alcohol with the ulcer area averaged at 68 mm 2 .
  • inventive composition with the wax homogenized with the oil is particularly effective in adhering to mucosa in the Gl tract and protecting it from the ulcerous effects of alcohol.
  • composition wherein beeswax adopts the pigeonhole structure with oil drops enclosed is presumed to adhere poorly and/or too slowly to the gastric mucosa before being exposed to alcohol.
  • the microcrystals of beeswax may be able to mix more readily with mucus in the Gl tract than beeswax in large particles or adopting a pigeonhole structure. It is also likely that in mixing with mucus, the microcrystals of beeswax induce the formation of an artificial membrane in a colloidal form to overlay the mucosa, thus protecting it from the ulcerous effects of alcohol. By adhering to the mucosa surface tightly, this artificial membrane may be able to improve microcirculation, to expand local ' mucous membrane capillary vessel, to accelerate circulation of blood and lymph, and to promote active metabolism of connective tissues.
  • the composition contains minimum amount of water, preferably less than 1%> by weight, more preferably less than 0.1%> by weight, and most preferably less than 0.01%> by weight.
  • beeswax also possesses many beneficial biochemical properties. Beeswax has long been used as an excipient for manufacturing drugs for external use.
  • beeswax is a drug for detoxication, granulation promotion, for relieving pain and cardialgia and treating diarrhea, pus and bloody stool, threatened abortion with vaginal bleeding, septicemia, refractory ulcer and thermal injury
  • a Dictionary of Chinese Materia Medica in Chinese, “Zhong Yao Da Ci Dian”, Science and Technology Press, Shanghai, 1986, page 2581.
  • beeswax can be grouped into four categories, i.e., esters, free acids, free alcohols and paraffins.
  • Beeswax also contains trace amount of essential oil and pigment.
  • esters there are myricyl palmitate, myricyl cerotate, and myricyl hypogaeate.
  • free acids there are cerotic acid, lignoceric acid, montanic acid, melissic acid, psyllic acid, hypogaeic acid and neocerotic acid.
  • ingredients of beeswax may also act in synergy with the active ingredients in the inventive composition (e.g., the sterol compound) to further promote general health and to cure various disorders of the body.
  • the active ingredients in the inventive composition e.g., the sterol compound
  • some ingredients may be able to enhance the phagocytic capacity of the mononuclear macrophage system as well as the permeability of histiocyte and body metabolism.
  • Some ingredients in beeswax may also have anti-inflammatory and anti-ulcer effects.
  • Octacosane alcohol contained in beeswax may be beneficial in reinforcing stamina, energy, and strength; enhancing muscle strength, increasing the reflex sensitivity; enhancing the body's ability to resist irritations from harmful substances; accelerating sex hormone secretion; inhibiting jerk; improving muscle and cardiac muscle function; and reducing systolic pressure and increase basal metabolic rate.
  • the composition may further comprise propolis at a concentration ranging from about 0.1 %> to 30%o by weight, more preferably from about 1%> to 20% by weight, and most preferably from about 5%> to 10%> by weight.
  • Propolis is known as a sticky, gum-like substance which is used to build the beehives.
  • intact propolis a variety of trace ingredients in form of a homogenous mixture with resins, beeswax, essential oils and pollens as predominant ingredients, as well as other ingredients such as flavonoids and phenol carboxylic acids.
  • Natural propolis hardly dissolves in water and has a peculiar odor.
  • Propolis can be prepared from beehives by extraction with organic solvents such as ethonol, ether and chloroform.
  • the ingredient contained in propolis may have the activity of resisting pathogenic micro-organism and anti-protoplast, enhancing immunologic function of human body, and promoting tissue regeneration and anti-oxidation.
  • the edible oil in the composition acts as a solvent to dissolve active ingredients and to disperse beeswax particles or microcrystals.
  • Sesame oil is preferably used for formulating the composition. Not wishing to be bound by the theory, the inventor believes that sesame oil may have the following beneficial effects on the body: 1) loosing the bowel to relieve constipation; 2) resisting inflammation, anti-infection, promoting tissue repair; 3) directly protecting gastric mucous membrane; 4) indirectly protecting gastric mucous membrane and against ulcers by accelerating gastric mucus secretion with oleic acid and linoleic acid contained in sesame oil; 5) antioxidation activity of ingredients contained in sesame oil including sesamol and Vitamin E which have strong antioxidation activity to eliminate free radical, protect the structure and function of the biomembrane, and protect gastrointestinal mucous membrane; 6) sesamin contained in sesame oil having effects of promoting metabolism of normal cell; 7) providing nutrition such as amino acids, lipids and micro
  • the inventive composition can be formulated readily by combining with pharmaceutically acceptable carriers that are well known in the art.
  • Such carriers enable the compounds to be formulated as tablets, pills, dragees, capsules, emulsions, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • the inventive composition is contained in capsules.
  • Capsules suitable for oral administration include push- fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push- fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the inventive composition is contained in soft capsules.
  • the inventive composition may be dissolved or suspended in suitable liquids, such as fatty oils or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • the inventive composition for oral use can be obtained by mixing the inventive composition with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings For this pu ⁇ ose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • the inventive composition may further comprise baicalin, preferably at a concentration ranging 0.01 to 5%> by weight, more preferably about 0.1 to 2%> by weight, and most preferably about 0.1 %> to 1 %> by weight.
  • baicalin may have anti-inflammatory effects on the damaged or diseased tissue, which helps providing a low inflammation environment for organ regeneration, mimicking that in scarless wound healing of a fetus at its early gestation stage. It might also be possible that baicalin may bind to cell membrane receptors for polysaccharides such as selectin and further promote cell adhesion.
  • baicalin beneficial effects include: 1) anti- inflammation; 2) anti-allergy; 3) anti- lipid peroxidation, presumably by inhibiting the formation of peroxide lipid and eliminating free radicals; 4) inhibiting platelet agglutination and accelerating blood circulation; 5) inhibiting spasm of intestinal smooth muscle and improving function of smooth muscle; 6) anti-pathogenic micro-organism such as bacteria, fungus and virus; and 7) detoxification, resulting in reduction in the intensity of spasm and decrease in mortality.
  • Baicalin may be obtained by extracting huangqin (Radix Scutellariae) in aqueous solution, oil, alcohol or other organic solvent, preferably in oil at temperature higher than 100°C, more preferably between about 120-200°C, and most preferably between about 160-180°C.
  • the root of huangqin is used and may be obtained from the plant selected from one or more members of the group of Scutellaria viscidula Bge, Scutellaria amoena C. H. Wright, Scutellaria rehderiana Diels, Scutellaria ikonnikovii Juz, Scutellaria likiangensis Diels and Scutellaria hypericifolia Levl of Labiatae Family. Dictionary of Chinese Materia Medica, Shanghai Science and Technology Press, 1988, pages 2017 to 2021.
  • the inventive composition may further comprise obaculactone (also called limonaic acid), preferably at a concentration ranging from about 0.01 to 5%> by weight, more preferably about 0.1 to 2%> by weight, and most preferably about 0.1%> to 1%) by weight.
  • Obaculactone may be obtained by extracting huangbai
  • obaculactone may also be obtained by extracting huangbai in alcohol such as ethanol.
  • the bark of huangbai is used and may be obtained from the plant selected from one or more members of the group of Phellodendron chinense Schneid, Plellodendron chinense Scheid var. glabriusculum Schneid, Phellodendron chinense Schneid var. omeiense Huang, Phellodendron Schneid var. yunnanense Huang and Phellodendron chinense Schneid var. falcutum Huang.
  • Phellodendron chinense Schneid var. falcutum Huang.
  • the inventive composition may further comprise obabenine, preferably at a concentration ranging from about 0.001%> to 2%> by weight, more preferably about 0.002%) to 0.5 % by weight, and most preferably about 0.003%> to 0.1% by weight.
  • Obabenine may be obtained by extracting huangqin, huangbai, and/or huanglian (coptis chinensis Franch) in aqueous solution, oil, alcohol or other organic solvent. Root of huanglian is preferably used.
  • Huanglian may be selected one or more from the group of Coptis deltoidea C. Y. Cheng et Hsiao, Coptis omeiensis (Chen) C. Y.
  • the inventive composition may further comprise berberine, preferably at a concentration ranging from about 0.001% to 2%> by weight, more preferably about 0.002%> to 0.5 % by weight, and most preferably about 0.003%) to 0.1% by weight.
  • the inventive composition may further comprise narcotoline, preferably at a concentration ranging from about 0.001%> to 2% by weight, more preferably about 0.002%) to 0.5 %> by weight, and most preferably about 0.003%> to 0.1% by weight.
  • Obabenine, berberine and narcotoline alone or in combination may suppress pain in the damaged tissue by inhibiting smooth muscle contraction.
  • the inventive composition may further comprise various amino acids, preferably all 18 natural amino acids, for providing nutrition support to cell growth.
  • the amino acids may be chemically synthesized or obtained from natural sources. For example, a full spectrum of natural amino acids may be obtained by extracting earthworms, a rich source of protein/amino acids, in oil or alcohol.
  • the inventive composition may further comprise nucleic acid bases such as adenine, cytidine, guanine, thymine and uridine.
  • the present invention provides methods for protecting and repairing mucosa, presumably by promoting the growth of regenerative mucosal cells.
  • physiological structure and function of the damaged or dysfunctional mucosa may be restored to enhance the body's ability to absorb nutrients, which, in turn, can improve the body's general health and strength the immune system to fight diseases.
  • a method for preventing ulceration or irritation of mucosa in the gastrointestinal tract of a host.
  • the method comprises: orally administering to the host a composition comprising an edible oil homogenized with an edible wax at a concentration ranging from 0.5 %> to 50%) by weight and a sterol compound at a concentration of at least 0.1%> by weight.
  • the host is preferably a human.
  • the composition may be administered to the host prior to consumption of alcohol, spicy food or other irritants to the stomach.
  • the composition may be administered to the host post consumption of these irritants to the stomach.
  • a method for treating a host having a gastrointestinal disorder comprises: orally administering to a host having a gastrointestinal disorder a composition comprising an edible oil homogenized with an edible wax at a concentration ranging from 0.5 %> to 50%> by weight and a sterol compound at a concentration of at least 0.1%> by weight.
  • the host is preferably a human.
  • the composition may be used as a pharmaceutical, a nutraceutical or a health food with or without a physician's prescription.
  • the dosing regimen may vary depending on the severity of the condition of the host.
  • the composition is preferably administered in an amount of 0.5-10 g per day, more preferably 2-8 g per day, and most preferably 3-6 g per day.
  • 0.5-10 g per day more preferably 2-8 g per day, and most preferably 3-6 g per day.
  • 1-10 capsules may be administered twice a day.
  • gastrointestinal disorders include, but are not limited to, gastrointestinal diseases, such as acute gastritis, chronic superficial gastritis, atrophic gastritis, antral gastritis, senile gastritis, bile-regurgitational gastritis, esophagitis, gastroduodenal ulcer, indigestion, gastric neurosis, constipation, as well as various consequent conditions including gastric hyperacidity, hypochlorhydria, flatulency, gastrointestinal discomfort after meals, gastritis caused by taking acidic drugs such as salicylates (e.g., aspirin), gastric discomfort after drinking, and gastric discomfort due to fasting.
  • gastrointestinal diseases such as acute gastritis, chronic superficial gastritis, atrophic gastritis, antral gastritis, senile gastritis, bile-regurgitational gastritis, esophagitis, gastroduodenal ulcer, indigestion, gastric neurosis, constip
  • a method for treating a patient having a gastrointestinal cancer comprises: orally administering to a patient having a gastrointestinal cancer a composition comprising an edible oil homogenized with an edible wax at a concentration ranging from 0.5 % to 50%> by weight and a sterol compound at a concentration of at least 0.1%> by weight.
  • the gastrointestinal (Gl) cancer can be an upper or lower Gl cancer.
  • the upper Gl cancer include, but are not limited to, 1) esophagus cancer; 2) stomach cancer; 3) pancreas cancer; 4) liver cancer; and 5) cancer of bile ducts.
  • the lower Gl cancer include, but are not limited to, cancers of the large bowel such as colorectal carcinoma, primary lymphomas, melanoma, and sarcoma of the large bowel.
  • the inventive composition may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art.
  • Sustained-release capsules may, depending on their chemical nature, release the inventive compositions for a few weeks up to over 100 days.
  • a pharmaceutical delivery vehicle for orally delivering a drug.
  • the pharmaceutical delivery vehicle comprises: an edible oil homogenized with an edible wax at a concentration ranging from 0.5%> to 50 %> by weight, wherein the edible wax forms microcrystals which are dispersed substantially uniformly in the edible oil at ambient temperature.
  • the size of the microcrystal is preferably between 0.1-100 ⁇ m, more preferably 5-70 ⁇ m, and most preferably 10-50 ⁇ m in length.
  • the form of the microcrystals may vary depending on the concentration and temperature. At ambient temperature, the microcrystal may adopt a single, needle-like crystal form and/or form a microcrystal complex by aggregating with each other.
  • composition may further comprise a sterol compound at a concentration preferably ranging from about 0.1%> to 20%o by weight, more preferably about 1%> to 10% by weight, and most preferably about 2%> to 6%> by weight.
  • the microcrystals of beeswax dispersed in sesame oil have a superior ability to adhere to mucosa and allow a sustained release of active ingredients dissolved in the oil or entrapped in the microcrystalls to reach mucosa and other tissues underneath. Further, owing the strong resistance of beeswax and sesame oil to acid and oxidation, the active ingredients included in the composition can be protected from decomposition in the acidic and oxidative environment of the stomach. These features are advantageous and desirable not only in enhancing the bioavailability but also in raising the therapeutic index of the active ingredient.
  • drugs can be formulated in the pharmaceutical base provided above.
  • the drugs are suitable for oral administration.
  • those drugs in other formulations that are deemed unsuitable for oral administration due to poor bioavailability may also be candidates for the combination with the pharmaceutical delivery vehicle of the present invention if such a combination results in improved bioavailability of the drugs.
  • the drug may be in the class of 1) gastrointestinal agents; 2) antibiotics; 3) antiviral agents; 4) antifungal agents 5) antineoplastic agents; 6) analgesics; 7) tranquilizers; 8) narcotic antagonists; 9) antidepressants; 10) antihistamines; 11) antimigraine; 12) cardiovascular drugs; 13) calcium channel blockers; 14) appetite suppressant; 15) contraceptive agents; 16) corticosteroids; 17) local anaesthetics; 18) diuretics; 19) antihypertensive agents; 20) steroids; 21) prostaglandins; 22) anti- inflammatory drugs; 23) antithrombotic agents; 24) cardiac glycosides; 25) antiparkinsonism; 26) chemical dependency drugs; 27) acidic drugs; and 28) peptides;
  • gastrointestinal agents include, but are not limited to, histamine H2 receptor antagonists such as nizatidine, famotidine, cimetidine, ranitidine, laxatives such as docusate sodium, bisacodyle, and antiemetics such as meclizine, metoclopramide, droperidol, haloperidol, and promethazine.
  • histamine H2 receptor antagonists such as nizatidine, famotidine, cimetidine, ranitidine
  • laxatives such as docusate sodium, bisacodyle, and antiemetics such as meclizine, metoclopramide, droperidol, haloperidol, and promethazine.
  • analgesics include, but are not limited to, bupreno ⁇ hine, codeine, fentanyl, mo ⁇ hine, and hydromo ⁇ hone.
  • anti- inflammatory drugs examples include, but are not limited to, ibuprofen, indomethacin, naproxen, diclofenac, tolfenamic acid, and piroxicam.
  • tranquilizers include, but are not limited to, diazepam, droperiodol, fluspirilene, haloperidol, and lorazepam.
  • cardiac glycosides examples include, but are not limited to, digoxin and ouabain,
  • narcotic antagonists include, but are not limited to, naloxone, and nalo ⁇ hine.
  • antiparkinsonism agents include, but are not limited to, bromocriptine, biperidin, benzhexol, and benztropine.
  • antidepressants include, but are not limited to, imipramine, nortriptyline, and pritiptylene.
  • antineoplastic agents include, but are not limited to, bleomycin, cyclosporin A, fluorouracil, mercaptopurine, methotrexate, camptothecin, paclitaxel, doxorubicin, and mitomycin.
  • antiviral agents include, but are not limited to, idoxuridine, acyclovir, interferons, AZT, and vidarabin.
  • antibiotic agents include, but are not limited to clindamycin, erythromycin, fusidic acid, gentamicin, and tetracyclin.
  • antifungal agents include, but are not limited to miconazole, ketoconazole, metronidazol, clotrimazole, amphotericin B, and nystatin.
  • appetite suppressants include, but are not limited to, fenfluramine, mazindol, and phentermin.
  • antihistamine examples include, but are not limited to, chlo ⁇ heniramine, terfenadine, and triprolidine.
  • antimigraine agents include, but are not limited to, dihydroergotamine, ergotamine, and pizotyline.
  • cardiovascular agents include, but are not limited to, nifedipine, diltiazem, glyceryl nitrate, isosorbide dinitrate, molsidomine, verapamil, and the like;
  • calcium channel blockers examples include, but are not limited to, verapamil, nifedipine, diltiazem, and nicardipine.
  • steroids examples include, but are not limited to, estradiol, estron, estriol, polyestradiol, polyestriol, dienestrol, diethylstilbestrol, dihydroergosterone, cyproterone, danazol, testosterone, progesterone, norethindrone, levonorgestrol, ethynodiol, norgestimate, gestanin, 3-keton-desogestrel, demegestone, promethoestrol, testosterone, spironolactone, and esters thereof,
  • antithrombotic examples include, but are not limited to, heparin, and warfarin.
  • diuretics include, but are not limited to, hydrochlorothiazide, flunarizine, and minoxidil.
  • antihypertensive agents include, but are not limited to, propanolol, metoprolol, clonidine, and pindolol.
  • Examples of chemical dependency drugs include, but are not limited to, nicotine, and methadone.
  • Examples of local anaesthetics include, but are not limited to, lidocaine, prilocaine, and benzocaine.
  • corticosteroids examples include, but are not limited to, beclomethasone, betamethasone, clobetasol, desonide, desoxymethasone, dexamethasone, diflucortolone, flumethasone, fluocinolone acetonide, fiuocinonide, hydrocortisone, methylprednisolone, triamcinolone acetonide, budesonide, and halcinonide.
  • acidic drugs examples include, but are not limited to, salicylates such as aspirin.
  • peptides include, but are not limited to, growth hormone releasing factors, growth factors (epidermal growth factor (EGF), nerve growth factor (NGF), TGF, PDGF, insulin growth factor (IGF), fibroblast growth factor (aFGF, bFGF.
  • growth factors epidermal growth factor (EGF), nerve growth factor (NGF), TGF, PDGF, insulin growth factor (IGF), fibroblast growth factor (aFGF, bFGF.
  • somatostatin calcitonin
  • insulin vasopressin
  • interferons IL-2
  • urokinase urokinase
  • serratiopeptidase superoxide dismutase
  • SOD tryrotropin releasing hormone
  • TRH tryrotropin releasing hormone
  • LH- RH luteinizing hormone releasing hormone
  • CRF corticotrophin releasing hormone
  • GHRH growth hormone releasing hormone
  • EPO colony stimulating factor
  • active ingredients for use according to the invention include azole derivatives such as, e.g., imidazoles and mazoles and derivatives thereof; nitro compounds such as, e.g., amyl nitrates, nitroglycerine and isosorbide nitrates; amine compounds such as, e.g., pilocaine, oxyabutyninchloride, lidocaine, benzocaine, nicotine, chlo ⁇ heniramine, terfenadine, triprolidine, propanolol, metoprolol and salts thereof; oxicam derivatives such as, e.g., piroxicam; mucopolysaccharides such as, e.g., thiomucasee; opoid compounds such as, e.g., mo ⁇ hine and mo ⁇ hine-like drugs such as bupreno ⁇ hine, oxymo ⁇ hone, hydromo ⁇ hone, levo ⁇
  • the purified sesame oil and huangqin (100 kg: 5kg) were added into a reaction tank, stirred and heated at 120°C for 50 minutes. The dreg was filtered and discarded. The filtrate was labeled as drug oil I.
  • drug oil I was pumped into another reaction tank, heated and mixed with purified beeswax which was kept warm at 85°C, at a weight ratio of 93kg:7kg (drug oil I : beeswax). The mixture was stirred adequately and the heating was stopped once the temperature reached 120°C. The mixture was stirred continuously for 20 minutes, resulting in drug oil II.
  • drug oil II was ground in a colloid mill with its gear distance adjusted to 0.6-0.8 ⁇ m and output speed at 15 Kg/15 min.
  • drug oil II can be homogenized at 6000 -10000 ⁇ m in a homogenizer at 40 + 2°C for 15-20 min.
  • the homogenized mixture was stirred at 100 ⁇ m and vacuumized to below 0.09 MP while the temperature was kept at 40 + 2°C for 50 min. When the temperature decreased to about 20°C and the degree of vacuum reached 0.6-0.8 MP, the homogenized drug oil II was allowed to stand for 20 minutes to obtain the content of the Gl capsules.
  • the content of Gl capsules were then filled in soft gel capsules made of gelatin and glycerin according to standard procedures. Briefly, gelatin and preservatives were added to a tank and soaked for 12 hours. With stirring and addition of water, glycerin and preservatives at appropriate proportions the mixture was heated at 65 °C to melt the gelatin. Upon complete melting of the gelatin, the mixture was vacuumized and kept warm for 2 hours with constant stirring, and then cooled to about 32 °C. On a soft gel capsule machine the content of Gl capsules (e.g., 500 mg/capsule) was filled into a shell made of gelatin and glycerin as described above. The capsule adopts an oval shape and its soft gel shell has a wall thickness of 0.7-0.8 mm.
  • Acute Toxicity Content of Gl Capsules was administered by oral gavage to Wistar rats (weight: 180-200 g) and Kunming mice (weight: 18-20 g) at various dosages specified in Tables 2 and 3. Sixteen hours before the administration of the test samples, feeding of the test animals was stopped. During the experiment period, all animals behaved normally with good hair color and brightness and no observable changes were found. The test results are summarized in Tables 2 and 3 for Wistar rats and Kunming mice, respectively. As shown in Tables 2 and 3, oral administration of the content of Gl Capsules did not cause any death of the tested animals even at exceedingly high dosages, e.g., 21.5 g/Kg.
  • lethal dose for causing death in half of the tested animal (LD 0 ) is estimated to be more than 21.5 g/Kg.
  • Kunming mice with weight of 24-28 g were divided into 5 groups, 10 in each group, 5 female and 5 male. Three dosage groups were given 100, 50, 10 times of 0.083 g/Kg (suggested daily dosage for human intake) of the content of Gl Capsules, i.e., 8.3 g/Kg, 4.2 g/Kg and 0.83 g/Kg, respectively. Two control groups, positive control (35 mg/Kg cyclophosphamide (CP)) and negative control (fed with normal food), were also adopted. All test samples were administered to the animals continuously for two days at an interval of 24 hours.
  • CP cyclophosphamide
  • negative control fed with normal food
  • Kunming mice with weight of 24-28 g were divided into 5 groups, 10 in each group. Three dosage groups were given 100, 50, 10 times of 0.083 g/Kg (suggested daily dosage for human intake) of the content of Gl Capsules, i.e., 8.3 g/Kg, 4.2 g/Kg and 0.83 g/Kg, respectively. Two control groups, positive control (35 mg/Kg cyclophosphamide (CP)) and negative control (fed with normal food), were also adopted. All test samples were administered to the animals continuously for two days at an interval of 24 hours.
  • CP cyclophosphamide
  • negative control fed with normal food
  • Gl Capsules The content of Gl Capsules was tested for laxative effects, i.e., the effects of the loosening the bowels to relieve constipation, on mouse models for constipation. Healthy Kunming mice were divided randomly into 5 groups, 20 in each group. Three dosage groups were adopted to test the content of Gl Capsules: the low dosage of 83.3 mg/kg body weight of the animal (BW) which is the suggested daily dosage for human); the moderate dosage 833 mg/kg BW (10 times of suggested daily dosage); and the high dosage 1666 mg/kg BW (20 times of suggested daily dosage).
  • BW body weight of the animal
  • the negative control group consists of 20 mice fed normally and the positive control group 20 mice fed with diphenoxylate at 50mg/kg BW.
  • mice were diluted with distilled water into required concentrations and volume of 0.1 ml/1 Og BW, and continuously administrated to the mice by oral gavage once a day for 14 days.
  • the mice were fed with normal food during this period.
  • mice were kept on fast for 24 hours overnight, but water was given.
  • the content of Gl Capsules were administered to mice in the three dosage groups by oral gavage.
  • diphenoxylate 50mg/kg
  • carbon ink 5% carbo activatus, 10% Arabic gum
  • mice in each subgroup All animals in each group were divided into two subgroups, 10 mice in each subgroup. One subgroup in each group was kept for observation of their dejection for 24 hours. The other was killed twenty minutes later and cut open the belly to measure the length of small intestine and the distance between pylorus and the front line of carbon ink to calculate carbon moving rates.
  • Table 7 shows the effects of the treatment on the weight of the mice in the five groups. As shown in Table 7, compared with the negative control group, the content of Gl Capsules did not cause any abnormal weight changes in mice within the tested dosage ranges.
  • Negative control group 20 19.6 ⁇ 1.2 25.8 ⁇ 0.9 29.7 ⁇ 1.3
  • Positive control group 20 19.5 ⁇ 1.2 25.3 ⁇ 0.9 29.2 ⁇ 1.4
  • Table 8 shows the effects of the treatment on dejection of the mice in the five groups. As shown in Table 8, the first dejection times and the total amounts of dejection in the three dosage groups are similar to that in the negative control group. In contrast, the positive control group in which the mice were induced by diphenoxylate to be constipated, had a much longer first dejection time and lower total amount of dejection. These results indicate that the content of Gl Capsules has laxative effects on constipated mice.
  • Negative control group 10 95.9 ⁇ 34.1* 36.9 ⁇ 4.6* 2.8 ⁇ 0.7*
  • Positive control group 10 230.6 ⁇ 56.0 16.4-13.6 1.0 ⁇ 0.2
  • Table 9 shows the moving rates of the bowel content stained with carbon ink in the mice in the five groups. As shown in Table 9, the moving rates in the three dosage groups are similar to that in the negative control group. In contrast, the positive control group had a much lower moving rate. These results confirm that the content of Gl Capsules could loosen the bowels to release constipation induced by diphenoxylate, thus having laxative effects on constipated mice.
  • Gl Capsules The content of Gl Capsules was tested for its activity in protecting the gastric mucosa of rats from ulcerative effects of anhydrous alcohol. Healthy Wistar male rats with weight of 60-100 g, were divided randomly into 5 groups, 10 in each group. Three dosage groups were adopted to test the content of Gl Capsules: the low dosage of 417 mg/kg; the moderate dosage of 834 mg/kg; and the high dosage of 1667 mg/kg, equivalent to 5, 10, and 20 times of the daily dose suggested for administration to human. Negative and positive control groups consisting of 10 rats each were also established.
  • Rats in the three dosage groups were administered by oral gavage with the content of Gl Capsules diluted with distilled water to the desired concentration and volumes (1 ml/lOOg weight), one time daily, for continuous 30 days. After the test, all of the experimental animals were kept on fast for 48 hours, but water was given. Afterwards, all animals except those in negative control group were administered with anhydrous alcohol (1 ml per animal) by gavage. On hour later, all animals were sacrificed and dissected. Theirs stomachs were immobilized with 1% formaldehyde and severity of injury on gastric mucosa was observed. Ulcerative indexes were calculated by measuring the length of streak injury if more than 1 mm, scoring 1 for every 1 mm streak, and double scoring if the width is larger than 1 mm. The cumulative scoring is the ulcerative index.
  • Table 10 lists ulcerative indexes of the rats in the five groups. As shown in Table 10, ulcerative indexes of the rats treated with the content of Gl Capsules are much lower than those of the rats in the positive control group. These results indicate that the content of Gl Capsules can protect the gastric mucosa from ulcerative effects of alcohol.
  • the composition comprises beeswax at 7% and sitosterol at about 1%, which are homogenized with a sesame oil extract of a combination of dry huangqin (2% w/w), huangbai (2% w/w), huanglian (2% w/w), poppy capsule (2% w/w) and earthworms (2% w/w).
  • Mucosa of small intestine (about 2 cm) was harvested from embryos of 16- day pregnant Kunming mice immediately after the sacrifice, cut into 1 mm x 1 mm pieces, and cultured in MEM in 12-well culture plates (2.5 ml medium/well, 5 mucosa pieces /well) by following a protocol in Donaldson and Kapadia (1980) "Organ culture of gastric mucosa: advantages and limitations" Methods in Cell
  • Figures 7A-H show the results of the in vitro experiments on mouse intestinal mucosa culture in the presence and absence of the inventive composition on days 24, 30, 38, 42, 50, 85, 90, and 97, respectively.
  • Pictures of the left column were obtained from the control group and those of the right column from the treatment group.
  • mucosa in both control and treatment maintained its integrity.
  • mucosa in both groups began to disintegrate into tiny tissue pieces, almost undetectable with naked eyes.
  • Under microscopic examination there appeared single cells and clones of cells in both groups.
  • cells in the control group gradually darkened, shrunk, and died. See left panels of Figures 7 A-H.
  • inventive composition is capable of not only promoting growth of mucosal cells of intestine, but also facilitating adhesion of cells to its cognate tissue and formation of mucosa in a culture.
  • the stuck contrast between the control group and the treatment group strongly indicates that the inventive composition has unique activities in stimulation of cell growth and adhesion in a tissue-specific matter.
  • the continuous growth of cells and the formation of mucosal tissue in the culture also suggest that regenerative stem cells might have been activated to produce large numbers of cells to sustain the growth and differentiation of mucosal cells, eventually leading to formation of mucosa in vitro. This is also consistent with the effects on mucosal cells in animal treated with the inventive composition.
  • in vitro experiments were designed to demonstrate that the inventive composition also has activities promoting the growth of mucosal cells and gastric tissue in an organ-specific manner.
  • Gastric tissue was harvested from mouse embryos and cultured in vitro. The tissue culture is divided into two groups: the control group cultured in normal tissue culture media (complete MEM) and the treatment group cultured in complete MEM with the addition of the inventive composition.
  • An embodiment of the inventive composition was used in the in vitro experiment.
  • the composition comprises beeswax at 7%, sitosterol at about 1%, obaculactone at about 0.5%, baicalin at about 0.3%, and .berberine at about 0.2%, which are mixed in sesame oil.
  • Gastric tissue of the whole stomach was harvested from embryos of 16-day pregnant Kunming mice immediately after the sacrifice, cut into 1 mm x 1 mm pieces, and cultured in MEM in 12-well culture plates (2.5 ml medium/well, 5 tissue pieces /well) by following a protocol in Donaldson and Kapadia (1980) "Organ culture of gastric mucosa: advantages and limitations" Methods in Cell Biology, Academic Press Inc, 2 IB: 349. About 3 g of the inventive composition was added to the treatment group and 3 ml of MEM was added to the control group. Growth medium in the cultures in both groups was changed every 4-5 days. The cultures were observed for 90 days and microscopic appearance of cultures was recorded.
  • Figures 8 A-H show the results of the in vitro experiments on mouse intestinal mucosa culture in the presence and absence of the inventive composition on days 24, 30, 38, 42, 50, 70, 85, 90, respectively.
  • Pictures of the left column were obtained from the control group and those of the right column from the treatment group.
  • gastric tissue in both control and treatment maintained its integrity.
  • Starting from the 8 th day of culture gastric tissue in both groups began to disintegrate into tiny tissue pieces, almost undetectable with naked eyes. Under microscopic examination, there appeared single cells and clones of cells in both groups. However, starting from the 18 th day of culture, cells in the control group gradually darkened, shrunk, and died. See left panels of Figures 8 - H
  • the inventive composition was also able to promote strong growth of gastric cells and formation of gastric tissue via tissue-specific cell-cell adhesion in vitro.
  • the continuous growth of cells and the formation of gastric tissue in the culture also suggest that regenerative stem cells, presumably epithelial stem cells, might have been activated to produce large numbers of cells to sustain the growth and differentiation of gastric cells, eventually leading to formation of gastric tissue in vitro. This is also consistent with the effects on gastric cells in animals treated with the inventive composition.

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Abstract

Cette invention a trait à de nouvelles compositions, ainsi qu'aux méthodes correspondantes, permettant à la fois de protéger et de stimuler la croissance cellulaire des muqueuses corporelles, notamment celles du tractus gastro-intestinal, et d'en restaurer la structure physiologique comme les fonctions. Il est possible d'utiliser cette composition comme agent pharmaceutique ou aliment fonctionnel et ce, afin de traiter un trouble gastro-intestinal ou d'améliorer la santé d'un animal, d'un humain, de préférence. Cette composition, qui se présente sous l'aspect d'une forme posologique à administrer oralement, contient une huile comestible, homogénéisée grâce à un composé à base de stérol, sous une concentration d'au moins 0,5 %, en pourcentage pondéral, ainsi qu'une paraffine comestible sous une concentration comprise, en pourcentage pondéral, entre 3 et 30 %. On peut également utiliser cette composition pour apporter au tractus gastro-intestinal d'autres ingrédients actifs et ce, dans le but de traiter divers états pathologiques.
PCT/US2002/034902 2001-10-30 2002-10-30 Methode permettant de reparer la muqueuse du tractus gastro-intestinal ainsi que d'en stimuler la regeneration et composition a cet effet Ceased WO2003037360A1 (fr)

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CA2464152A CA2464152C (fr) 2001-10-30 2002-10-30 Methode permettant de reparer la muqueuse du tractus gastro-intestinal ainsi que d'en stimuler la regeneration et composition a cet effet
EP02773952A EP1439847B1 (fr) 2001-10-30 2002-10-30 Methode permettant de reparer la muqueuse du tractus gastro-intestinal ainsi que d'en stimuler la regeneration et composition a cet effet
JP2003539703A JP4464133B2 (ja) 2001-10-30 2002-10-30 胃腸管における粘膜組織を修復および再生を促進するための方法および組成物
AT02773952T ATE510549T1 (de) 2001-10-30 2002-10-30 Verfahren und zusammensetzung zur reparatur und förderung der regeneration von schleimhautgewebe im magen-darm-trakt

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US11623010B2 (en) 2018-08-29 2023-04-11 Li Li Pharmaceutical carrier in the preparation of an anti-diabetic pharmaceutical composition and methods for treatment

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CA2464152A1 (fr) 2003-05-08
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US7919123B2 (en) 2011-04-05
EP1439847B1 (fr) 2011-05-25
US20040115243A1 (en) 2004-06-17
EP1439847A1 (fr) 2004-07-28
EP1439847A4 (fr) 2005-12-14
CN1417326A (zh) 2003-05-14
US20070166374A1 (en) 2007-07-19
JP2005508976A (ja) 2005-04-07
US20060198898A1 (en) 2006-09-07
US7211276B2 (en) 2007-05-01
ATE510549T1 (de) 2011-06-15
US6685971B2 (en) 2004-02-03
US7399492B2 (en) 2008-07-15
CA2464152C (fr) 2010-09-28
US20030091651A1 (en) 2003-05-15
CN1955280B (zh) 2013-08-28
US7074438B2 (en) 2006-07-11
CN1818058A (zh) 2006-08-16
US20080096854A1 (en) 2008-04-24

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